The long term objective of this Pediatric SCOR is to determine the molecular bases of defective human cardiac morphogenesis and myocardial function which results in congenital heart disease (CHD) and pediatric cardiomyopathy (CM). The underlying hypothesis is that single gene defects at multiple loci in the human genome cause most pediatric cardiac structural and myopathic diseases. Two corollaries will also be explored, that (i) genetic abnormalities at the same locus have variable expressivity and can result in different phenotypes and (ii) genotype- phenotype correlations exist. A multi-disciplinary approach encompassing 14 investigators, 6 clinical and laboratory projects, and 4 core units at three locations is proposed. Molecular genetic studies of a St. Louis family with dominantly-inherited dilated CM; CM or sudden death secondary to mutations in mitochondrial fatty acid oxidation enzymes; patients with CHD associated with at the human at the human 8p23 locus encompassing the GATA-4 gene, a critical transcription factor in heart; elastin in heart; elastin mutations in supravalvar aortic stenosis; and dominantly-inherited atrial septal defects (ASD) mapped to 5p and 5q are the clinical focus. Mouse gene ablation and transgenic models to delineate (i) the pathogenesis of CM and sudden death in fatty acid oxidation defects, (ii) the essential role and downstream targets of GATA-4 expressed in mouse embryonic endoderm for mesoderm-mediated and downstream morphogenesis, (iii) the mechanisms by which elastin mutations disrupt elastic fiber assembly and vasculogenesis, and (iv) the mechanisms by which mutant mouse homologs of genes defective in human familial ASD result in CHD will be created. The molecular role of syndecans in determination of left-right asymmetry will be studied in the uniquely-manipulable Xenopus embryo system as a model for mechanisms underlying human heterotaxy syndromes and CHD. Characterization of defective human genes causing pediatric heart disease and the mechanisms through which mutations alter cardiac development and myocardial function is necessary before manipulations to prevent CHD and inherited CM are feasible.